This application Nicotine's Effects on Other Drugs of Abuse, investigates conditions under which nicotine may alter the reinforcing, subjective and physiologic effects of the two most widely used psychoactive drugs in the United States, marihuana and ethanol. Even though these substances are commonly used together, the medical consequences, pharmacokinetic profiles and reinforcing effects of these drug combinations are not well understood. The proposed studies will systematically assess whether nicotine pretreatment via a transdermal patch alters the pharmacodynamics and pharmacokinetics of acute marihuana and ethanol and will evaluate whether these interactions are dose- dependent. Study 1 will investigate these interactions in non-smokers in order to characterize the nature of the pharmacodynamic interactions without the possible confounds introduced by variables associated with smoking. Studies 2-5 will use moderate tobacco smokers as subjects in an attempt to replicate conditions similar to those experienced by individuals who are treating their nicotine dependence with the patch and may continue to smoke marihuana or drink alcohol. These studies will also investigate whether nicotine alters ethanol's or marihuana's reinforcing effects by using a laboratory-based drug self-administration paradigm. In addition, because there is a paucity of research studies using women as subjects, and sex-related differences have been shown in the absorption, bioavailability, distribution and metabolism of various drugs of abuse, both male and female occasional drug users will be used in the studies to identify gender differences in the effects of these drug interactions. Finally, the influence of hormonal fluctuations associated with the menstrual cycle on the observed drug interactions will be investigated by studying women at different times of their menstrual cycle. The findings from the proposed studies will provide important information on the pharmacodynamic interactions and the reinforcing effects of these drug combinations. These findings will have direct public health implications because, since the nicotine transdermal patch is now over-the-counter, many individuals may be using it without medical supervision and at the same time using or abusing alcohol and other drugs. If nicotine increases the positive effects and decreases the negative effects of ethanol and marihuana, individuals using a nicotine transdermal patch may find these substances more reinforcing and may be more likely to increase their use, putting them at higher risk for developing dependence.